OBJECTIVE Retrospective clinical data and case studies support a therapeutic effect of ketamine in suppression of spreading depolarization (SD) following brain injury. Preclinical data strongly support efficacy in terms of frequency of SD as well as recovery from electrocorticography (ECoG) depression. The authors present the results of the first prospective controlled clinical trial testing the role of ketamine used for clinical sedation on occurrence of SD. METHODS Ten patients with severe traumatic brain injury (TBI) or aneurysmal subarachnoid hemorrhage (SAH) were recruited for this pilot trial. A standard ECoG strip was placed at the time of craniotomy, and the patients were then placed on an alternating every-6-hour schedule of ketamine or other sedation agent. The order of treatment was randomized. The ketamine dose was adjusted to clinical effect or maintained at a subanesthetic basal dose (0.1 mg/kg/hr) if no sedation was required. SD was scored using standard criteria, blinded to ketamine dosing. Occurrence of SD was compared with the hourly dose of ketamine to determine the effect of ketamine on SD occurrence. RESULTS Successful ECoG recordings were obtained in all 10 patients: 8 with SAH and 2 with TBI. There were a total of 1642 hours of observations with adequate ECoG: 833 hours off ketamine and 809 hours on ketamine. Analysis revealed a strong dose-dependent effect such that hours off ketamine or on doses of less than 1.15 mg/kg/hr were associated with an increased risk of SD compared with hours on doses of 1.15 mg/kg/hr or more (OR 13.838, 95% CI 1.99-1000). This odds ratio decreased with lower doses of 1.0 mg/kg/hr (OR 4.924, 95% CI 1.337-43.516), 0.85 mg/kg/hr (OR 3.323, 95% CI 1.139-16.074), and 0.70 mg/kg/hr (OR 2.725, 95% CI 1.068-9.898) to a threshold of no effect at 0.55 mg/kg/hr (OR 1.043, 95% CI 0.565-2.135). When all ketamine data were pooled (i.e., on ketamine at any dose vs off ketamine), a nonsignificant overall trend toward less SD during hours on ketamine (χ = 3.86, p = 0.42) was observed. CONCLUSIONS Ketamine effectively inhibits SD over a wide range of doses commonly used for sedation, even in nonintubated patients. These data also provide the first prospective evidence that the occurrence of SD can be influenced by clinical intervention and does not simply represent an unavoidable epiphenomenon after injury. These data provide the basis for future studies assessing clinical improvement with SD-directed therapy. Clinical trial registration no.: NCT02501941 (clinicaltrials.gov).
Objectives: To characterize emergency department sedation practices in mechanically ventilated patients, and test the hypothesis that deep sedation in the emergency department is associated with worse outcomes. Design: Multicenter, prospective cohort study. Setting: The emergency department and ICUs of 15 medical centers. Patients: Mechanically ventilated adult emergency department patients. Interventions: None. Measurements and Main Results: All data involving sedation (medications, monitoring) were recorded. Deep sedation was defined as Richmond Agitation-Sedation Scale of –3 to –5 or Sedation-Agitation Scale of 2 or 1. A total of 324 patients were studied. Emergency department deep sedation was observed in 171 patients (52.8%), and was associated with a higher frequency of deep sedation in the ICU on day 1 (53.8% vs 20.3%; p < 0.001) and day 2 (33.3% vs 16.9%; p = 0.001), when compared to light sedation. Mean (sd) ventilator-free days were 18.1 (10.8) in the emergency department deep sedation group compared to 20.0 (9.8) in the light sedation group (mean difference, 1.9; 95% CI, –0.40 to 4.13). Similar results according to emergency department sedation depth existed for ICU-free days (mean difference, 1.6; 95% CI, –0.54 to 3.83) and hospital-free days (mean difference, 2.3; 95% CI, 0.26–4.32). Mortality was 21.1% in the deep sedation group and 17.0% in the light sedation group (between-group difference, 4.1%; odds ratio, 1.30; 0.74–2.28). The occurrence rate of acute brain dysfunction (delirium and coma) was 68.4% in the deep sedation group and 55.6% in the light sedation group (between-group difference, 12.8%; odds ratio, 1.73; 1.10–2.73). Conclusions: Early deep sedation in the emergency department is common, carries over into the ICU, and may be associated with worse outcomes. Sedation practice in the emergency department and its association with clinical outcomes is in need of further investigation.
Levetiracetam used as a second-line agent was associated with control of drug-induced seizures and prevention of seizure recurrence without obvious adverse effects. A prospective study is needed to confirm these results.
Background Antipyretic therapy is commonly prescribed to patients with infection, but its impact on clinical outcomes has yielded mixed results. No data currently exist to characterize the use of antipyretic medications in patients with severe sepsis or septic shock. Objective We sought to identify clinical and demographic factors associated with antipyretic medication administration in severe sepsis and septic shock. Methods Single-center retrospective cohort study of all febrile patients (Tmax ≥ 38.3°C) at a 1,111-bed academic medical center with gram-negative severe sepsis or septic shock between January 2002 and February 2008. Patients were excluded for liver disease, acute brain injury, and allergy to acetaminophen. Generalized estimating equations were used to estimate the effect of clinical factors on treatment of patients with antipyretic medications. Results Although 76% of patients in this febrile cohort (n = 241) had an order for an antipyretic agent, only 42% received antipyretic therapy and 95% of antipyretic doses were acetaminophen. Variables associated with antipyretic treatment were temperature (OR 2.11/°C, 1.53 – 2.89), time after sepsis diagnosis (OR 0.88/8 hrs, 0.82 – 0.95), surgery during hospitalization (OR 0.49, 0.31 – 0.80), death within 36 hours (OR 0.35, 0.15 – 0.85), and mechanical ventilation (OR 0.58, 0.34 – 0.98). Conclusions Most febrile episodes in patients with gram-negative severe sepsis or septic shock were not treated with antipyretic medications. Treatment factors predicted antipyretic therapy, but severity of illness factors, demographic factors, and location in the hospital did not.
BACKGROUND Severe traumatic brain injury (TBI) requires individualized, physiology-based management to avoid secondary brain injury. Recent improvements in quantitative assessments of metabolism, oxygenation, and subtle examination changes may potentially allow for more targeted, rational approaches beyond simple intracranial pressure (ICP)-based management. The authors present a case in which multimodality monitoring assisted in decision-making for decompressive craniectomy. OBSERVATIONS This patient sustained a severe TBI without mass lesion and was monitored with a multimodality approach. Although imaging did not seem grossly worrisome, ICP, pressure reactivity, brain tissue oxygenation, and pupillary response all began worsening, pushing toward decompressive craniectomy. All parameters normalized after decompression, and the patient had a satisfactory clinical outcome. LESSONS Given recent conflicting randomized trials on the utility of decompressive craniectomy in severe TBI, precision, physiology-based approaches may offer an improved strategy to determine who is most likely to benefit from aggressive treatment. Trials are underway to test components of these strategies.
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